Bazedoxifene

Mechanism of Action

Bazedoxifene belongs to the category of SERMs and is a member of the interleukin-6 cytokine family. Bazedoxifene's mode of action varies depending on the targeted tissue or estrogen receptor. In cases of breast cancer or uterine carcinoma/endometrial hyperplasia, bazedoxifene acts as a competitive antagonist, yielding antiproliferative effects. Conversely, the drug acts as an agonist by stimulating lipid metabolism and ensuring proper regulation of bone turnover.[11] 

The biomolecular antagonistic effects arise from a pro-apoptotic signal, enabling bazedoxifene to inhibit STAT3 and MAPK signaling pathways and effectively eliminate cancer cells.[12] This drug has an oral bioavailability of around 6%, exhibiting a linear increase in serum concentration in response to ascending dosage levels. Although the molecular mechanism by which an estrogen agonist such as bazedoxifene modulates bone regulation and remodeling is not fully elucidated, current hypotheses suggest reductions in osteoclastogenesis through mitochondrial and ER-mediated mechanisms, coupled with underlying effects on regulating serum calcium levels.[13]

Pharmacokinetics

Absorption: Healthy postmenopausal women were administered multiple doses of 20 mg bazedoxifene, and on the tenth day, the mean steady-state pharmacokinetic parameters were measured. The Tmax for bazedoxifene is 2.5 ± 2.1 h, and the area under the curve (AUC) was 71 ± 34 ng·h/mL. Baseline-adjusted total estrone has a Tmax of 6.5 ± 1.6 h and an AUC of 35 ± 12 ng·h/mL for conjugated estrogens. Food increases bazedoxifene's AUC by 25%, but Cmax remains unchanged. The absolute bioavailability of bazedoxifene is about 6%.[14]

Distribution: The volume of distribution for bazedoxifene is 14.7 ± 3.9 L/kg. Endogenous and exogenous estrogens are similarly distributed throughout the body, with higher concentrations in target organs for sex hormones. Estrogens are predominantly transported in the blood, primarily bound to sex hormone-binding globulin (SHBG) and albumin. Bazedoxifene binds strongly (98% to 99%) to plasma proteins but not to SHBG and is believed to undergo enterohepatic recycling. Therefore, it is evident that certain medications may interfere with the recycling of bazedoxifene, altering its systemic exposure.

Metabolism: Exogenous estrogens undergo metabolism similar to endogenous estrogens. In circulation, estrogens maintain a dynamic equilibrium through metabolic interconversions. The reversible conversion of 17-β estradiol to estrone and their subsequent transformation to estriol, the primary urinary metabolite, is crucial for maintaining this equilibrium. In postmenopausal women, estrone sulfate, serving as a circulating reservoir for forming more active estrogens, constitutes a significant proportion of circulating estrogens, particularly as sulfate conjugates. Bazedoxifene undergoes extensive metabolism primarily through glucuronidation by uridine diphosphate (UDP) glucuronosyltransferase (UGT), notably in the intestinal wall (UGT1A8 and UGT1A10).[15][16] The major circulating metabolite is bazedoxifene-5-glucuronide, with concentrations in plasma approximately 10-fold higher than that of the unchanged drug.

Elimination: After administering conjugated estrogens/bazedoxifene, the elimination half-life for baseline-adjusted total estrone is approximately 17 hours, while bazedoxifene has a half-life of around 30 hours. The excretion of 17-β-estradiol, estrone, estriol, and their glucuronide and sulfate metabolites occurs primarily in the urine. The primary elimination pathway for bazedoxifene is biliary excretion, with approximately 85% of the dose excreted in feces and less than 1% in urine.[3]

Administration

The combination drug regimen of conjugated estrogens and bazedoxifene is strongly considered, alongside bisphosphonates, as the first-line treatment for postmenopausal women at risk of osteoporosis, hot flashes, or night sweats.

Available Dosage Forms and Strengths

Bazedoxifene is provided in a fixed-dose combination of 20 mg bazedoxifene and 0.45 mg conjugated estrogen tablets for oral administration.

Adult Dosing

As per FDA-approved indications, the recommended daily dosage for managing vasomotor symptoms associated with menopause and preventing postmenopausal osteoporosis is 1 tablet daily. This pharmaceutical agent is typically supplied as a 30-day package, and the average treatment duration spans approximately 2 years. In most instances, women are advised to take this medication with 600 mg of calcium or vitamin D supplements. Healthcare providers do not recommend exceeding the dosage threshold and not consuming more than 1 tablet within 24 hours. In case of a missed dose, patients are explicitly instructed to take the oral medication as soon as possible, without regard to the timing of meals.[17]

Specific Patient Populations

Hepatic impairment: Bazedoxifene/conjugated estrogen is contraindicated in patients with hepatic impairment.[18]

Renal impairment: Bazedoxifene/conjugated estrogen is not recommended in patients with renal impairment due to the risk of fluid retention caused by estrogens.

Breastfeeding considerations: Estrogens can reduce milk production in breastfeeding mothers. Currently, information about the presence of bazedoxifene in human or animal breast milk and its potential effects on milk production or the nursing infant is insufficient. Based on its mechanism of action, it is believed that bazedoxifene may inhibit the essential functions of estrogen in mammary tissue during lactation. 

Pregnancy considerations: Bazedoxifene/conjugated estrogen is contraindicated for use in pregnant women.

Pediatric patients: Bazedoxifene/conjugated estrogen is not indicated for use in children.

Older patients: Bazedoxifene/conjugated estrogen is not recommended in women 75 and older.

Adverse Effects

Based on the results analyzed in placebo-controlled trials, the most frequent adverse effects associated with the combination of conjugated estrogens and bazedoxifene include muscle spasms, nausea, diarrhea, dyspepsia, abdominal pain, oropharyngeal pain, neck pain, and dizziness.

Although other adverse effects and complications were associated with bazedoxifene/conjugated estrogens, the probability of exhibiting those symptomatic adverse effects was not significantly different from what was observed in the placebo group.[18] Bazedoxifene/conjugated estrogen treatment is associated with an increased risk of venous thromboembolism. In addition, conjugated estrogen is associated with exacerbation of asthma, diabetes mellitus, epilepsy, migraine, hereditary angioedema, elevated blood pressure, hypocalcemia, fluid retention, and gallbladder disease.[18]

Drug-Drug Interactions

Cytochrome P450–mediated interactions: Research on drug-drug interactions with bazedoxifene/conjugated estrogens is currently limited. Estrogens undergo partial metabolism by cytochrome CYP3A4. Simultaneous administration of itraconazole, a potent CYP3A4 inhibitor, with bazedoxifene/conjugated estrogen leads to increased exposure to bazedoxifene and, to a lesser extent, conjugated estrogens.[17] In contrast, inducers of CYP3A4, such as phenobarbital, carbamazepine, St John’s wort, and rifampin, can decrease estrogen concentrations, leading to reduced efficacy and alterations in the uterine bleeding profile.

UGT-mediated interactions: Bazedoxifene undergoes metabolism by UGT enzymes in the intestine and liver.[16] Concurrent use of medications that induce UGT, such as phenobarbital, rifampin, carbamazepine, and phenytoin, may enhance metabolism, potentially leading to reduced bazedoxifene exposure and an increased risk of endometrial hyperplasia.[18] Appropriate diagnostic measures, including endometrial sampling, should be considered for postmenopausal women experiencing persistent or recurrent abnormal genital bleeding.

Contraindications

Bazedoxifene combined with conjugated estrogens belongs to the SERM class of drugs, but it has some contraindications similar to other drugs in this class. Pregnancy is the most significant contraindication, as the FDA has classified the combination of bazedoxifene/conjugated estrogens as pregnancy category X drugs. Notably, bazedoxifene, on its own, is not a potential teratogen.

Other notable contraindications include abnormal uterine bleeding, hypersensitivity or allergic reactions to exogenous estrogen, and certain cardiovascular complications, including any previous or current history of DVT, stroke, pulmonary embolism, or myocardial infarction. Patients with hepatic impairment are strongly advised against using this drug as it may result in unintended pharmacological effects due to ineffective metabolism by CYP3A4 and inadequate drug clearance. A history of thrombophilic disorders, such as proteins C and S and antithrombin deficiency, constitutes a contraindication to using bazedoxifene/conjugated estrogens.[19]

Box Warnings

Endometrial cancer: Unopposed estrogen therapy is associated with an increased risk of endometrial cancer, with the risk being influenced by the duration of treatment and estrogen dose. Notably, prolonged use of estrogen therapy heightens the risk. Women using bazedoxifene/conjugated estrogens should refrain from additional estrogen intake, as it may increase the risk of endometrial hyperplasia, potentially leading to endometrial cancer. Clinical surveillance of all women taking bazedoxifene/conjugated estrogens is essential. Postmenopausal women with abnormal genital bleeding should undergo diagnostic measures, including endometrial sampling, to rule out malignancy.[18]

Cardiovascular disorders and dementia: According to the Women's Health Initiative (WHI), postmenopausal women treated with a daily oral dosage of 0.625 mg conjugated estrogens alone for 7.1 years face a higher risk of DVT and stroke compared to those who received a placebo. Furthermore, the WHI Memory Study (WHIMS) discovered that postmenopausal women 65 and older, undergoing a 5.2-year treatment with 0.625 mg of conjugated estrogens alone, exhibited an increased risk of possible dementia compared to the placebo group. Notably, the estrogen-alone substudy of the WHI exclusively examined the effects of a daily oral dosage of 0.625 mg conjugated estrogens. Thus, it remains uncertain whether the observations from the WHI regarding adverse cardiovascular events and dementia apply to lower conjugated estrogen doses, alternative administration routes, or other estrogen-alone products. Physicians must consider a patient's profile when assessing the risks and benefits of estrogen therapy. To ensure that the treatment aligns with individual goals, it is recommended to prescribe estrogens at the lowest effective dose for the shortest duration possible.

Monitoring

Before initiating any treatment with bazedoxifene and conjugated estrogens, obtaining a quantitative evaluation of bone health and thoroughly assessing potential osteoporosis risks is crucial. Dual-energy x-ray absorptiometry (DEXA) is the preferred diagnostic tool for measuring BMD. A DEXA scan is an imaging device that uses spectral imaging to determine BMD scores and analyze the long-term probability of developing a vertebral or hip fracture. After initiating bazedoxifene/conjugated estrogens treatment, it is crucial to monitor BMD scores through DEXA regularly scans every 1 to 2 years. The frequency of monitoring can be adjusted based on the overall improvement in bone strength over time.[20]

Following initiation of bazedoxifene/conjugated estrogen therapy, it is integral for both the patient and healthcare provider to monitor for any potential cardiovascular adverse effects vigilantly. There is documented evidence indicating that prolonged use of estrogen agonists/antagonists among postmenopausal women is associated with an elevated risk of stroke, pulmonary embolism, and DVT.

If a patient experiences symptoms indicative of a cardiovascular anomaly, they must discontinue the medication immediately and report the symptoms to their primary healthcare provider or a cardiologist. The patient should inform their primary care physician of a family history of cardiovascular complications. This allows for an assessment to determine whether exploring alternative drug regimens or implementing rigorous monitoring for symptoms within a healthcare setting is advisable. Additional adverse effects that require monitoring but do not pose an immediate danger to a patient include abdominal pain, nausea, muscle spasms, and light-headedness.[17]

Another potential long-term concern associated with unopposed estrogen therapy is the risk of endometrial cancer. Clinical trials have indicated a slight increase in the risk of endometrial hyperplasia following treatment with 20 mg bazedoxifene/0.625 mg conjugated estrogens compared to the treatment group receiving only 20 mg bazedoxifene/0.45 mg conjugated estrogens. No instances of endometrial hyperplasia were reported in the placebo group. Although the risk of endometrial cancer is relatively low for postmenopausal women using conjugated estrogens/bazedoxifene, it is crucial to avoid supplementing this drug with any additional estrogen therapy and to maintain diligent clinical surveillance throughout drug therapy.[21]

Toxicity

Signs and Symptoms of Overdose

Potential symptoms of an overdose of bazedoxifene/conjugated estrogens include severe muscle spasms and classic gastrointestinal symptoms, including abdominal pain, vomiting, and nausea. Current research has not found an antidote or first-line treatment to reverse a potentially toxic dose of this combination drug. Patients are advised to promptly seek the services of an emergency room or contact a poison control center if they suspect an overdose.

Clinical demonstrations have shown that bazedoxifene possesses a broad therapeutic index as a standalone pharmaceutical agent. Although bazedoxifene is FDA-approved at a 20 mg dose with conjugated estrogens, it has been shown to have no toxicity effects even at doses up to 80 mg.[11]

In comparison to conjugated estrogen, bazedoxifene is considered a safer drug with minimal risk of long-term adverse effects or overdose toxicity. In the quest to determine the optimal ratio of bazedoxifene to conjugated estrogens, a double-blind, randomized, placebo-controlled clinical study revealed that a dose of 0.625 mg of conjugated estrogen significantly increased endometrial thickness. Furthermore, it was established that a minimum of 20 mg of bazedoxifene was required to mitigate the hyperplasia effects induced by conjugated estrogen and reduce the likelihood of long-term development of endometrial carcinoma.[22]

In addition, bazedoxifene/conjugated estrogens pose significant risks due to their teratogenic effects on fetal development, leading to their classification as a pregnancy category X drug. If a patient discovers she is pregnant while undergoing bazedoxifene/conjugated estrogen drug therapy, it is recommended to immediately discontinue the medication and consult with her primary care physician or obstetrician.

Enhancing Healthcare Team Outcomes

Bazedoxifene is a SERM used with conjugated estrogen to treat osteoporosis and hot flashes in postmenopausal women. Since its FDA approval in late 2013, this drug has gained increased clinical acceptance within the physician community. However, using this drug requires effective interprofessional communication among the patient's healthcare management team, especially considering its specific target population with particular symptoms.

In prior phases, randomized and double-blind clinical trials were carried out to assess the efficacy of conjugated estrogens/bazedoxifene in postmenopausal women. Most data indicate the drug's effectiveness for women between 40 and 65. The drug is contraindicated for women 75 and older.[23]

Before taking this drug, a woman may want to consult several clinicians, including her primary care physician, gynecologist, endocrinologist, or orthopedic surgeon, depending on the severity of her osteoporosis or accompanying fractures. Collaborating with various physicians can offer the patient a comprehensive understanding of the drug's benefits and significant contraindications. Nurses are critical as frontline administrators of drugs, monitoring patients and providing a comprehensive assessment of overall clinical status, adherence, and improvement. Pharmacists contribute by advising the team on medication interactions and assessing dosing requirements for patients with comorbidities to prevent adverse events.

Lack of proper management and care coordination by healthcare providers may lead to adverse effects following the usage of this drug. In the event of an overdose or a significant adverse drug reaction requiring an emergency room visit, the attending emergency room clinician must be able to communicate with the patient's primary care physician and potentially another specialist who had the most frequent visits with the patient or prescribed bazedoxifene/conjugated estrogens.[23]

The primary care physician is crucial in educating patients on the significance of incorporating behavioral modifications into their pharmaceutical regimen. For a postmenopausal woman, regular exercise and a nutritious diet are imperative to promote a healthy weight, reducing susceptibility to brittle bones and compounding fractures. In addition, it is pivotal for the patient to refrain from alcohol, smoking, and spicy foods, as these may exacerbate hot flashes symptoms.

Lifestyle changes complement the effects of bazedoxifene/conjugated estrogens, and healthcare professionals must be proficient in facilitating necessary lifestyle adjustments alongside a targeted drug treatment plan to enhance patient-centered care. Open and clear communication reduces rapid diagnosis and treatment decisions, preventing errors and ensuring a coordinated response. An interprofessional team, including clinicians (MDs, DOs, NPs, and PAs), pharmacists, specialists, and nurses, must communicate effectively to optimize patient outcomes and minimize adverse drug reactions associated with bazedoxifene therapy.